Mechanisms Regulating Innate Immune Responses

项目摘要/摘要 宿主之间的相互作用：微生物的相互作用在粘膜表面是至关重要的。失调症 这些相互作用可能导致肠道炎症性疾病，如炎症性肠病 (IBD)。对微生物的识别和反应最初是由模式识别受体介导的 (PRR)。PRR反应导致细胞因子的分泌和细胞的激活，以及微生物 通行证。这些结果之间的平衡会影响炎症性疾病的易感性 疾病和传染病。我们的长期目标是了解介导IBD的机制 从而最终改善人类IBD的管理和治疗。 IRF5区域的多态与一系列免疫介导性疾病有关， 包括IBD。我们发现，IRF5是影响机体免疫功能的最重要的遗传决定因素。 来自髓系细胞的PRR启动的信号和细胞因子的个体差异 人群：IRF5疾病风险基因的携带者在 对一系列PRR刺激的反应。尽管IRF5在调节个体间的关系方面很重要 人髓系PRR诱导的细胞因子的变化，IRF5在IBD中的作用 体内发病机制尚未被研究(SA IC和IIC)。IBD发病机制的关键是 髓系细胞清除微生物；然而，IRF5如何调节驻留和 致病肠道微生物未知(SA III)。多个细胞亚群对肠道有贡献 免疫失调，以及对IRF5-/-小鼠的有限体内研究也证明了 在狼疮模型系统中，IRF5在T细胞结果中，伴随着Th1分化的减少。然而， IRF5是以T细胞内源性(SA I)还是T细胞外源性(SA II)的方式调节T细胞的结果 未知，包括在肠道组织中。我们假设IRF5将有助于 免疫细胞在体内肠道免疫动态平衡中的作用 髓样细胞和T细胞亚群，尽管它可能导致结肠炎的炎症结果，但它 对于调节肠道病原体是必不可少的。我们进一步假设与IRF5 IBD相关 多态将调节IRF5在这些相关免疫结果中所识别的角色。我们 将把对人类原代细胞的研究与对小鼠体内的研究相结合，以剖析IRF5的贡献 对IBD发病机制的研究

Project Summary/Abstract The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in the IRF5 region are associated with a wide-range of immune-mediated diseases, included IBD. We found that IRF5 is the single most important genetic determinant of the inter- individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, how IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA IC&IIC). Key to IBD pathogenesis is the ability of myeloid cells to clear microbes; however, how IRF5 regulates clearance of both resident and pathogenic intestinal microbes is not known (SA III). Multiple cell subsets can contribute to intestinal immune dysregulation, and limited in vivo studies in IRF5-/- mice have also demonstrated a role for IRF5 in T cell outcomes, with decreased Th1 differentiation in lupus model systems. However, whether IRF5 regulates T cell outcomes in a T cell-intrinsic (SA I) or T cell-extrinsic (SA II) manner is not known, including in intestinal tissues. We hypothesize that IRF5 will contribute to multiple immune cell functions essential in intestinal immune homeostasis in vivo through its role in both myeloid and T cell subsets, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens. We further hypothesize that IRF5 IBD-associated polymorphisms will modulate the identified roles for IRF5 in these pertinent immune outcomes. We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis